Transglutaminases are a group of calcium-dependent enzymes that catalyze the formation of ε-(γ-glutaminyl) lysine isopeptide bonds between protein-bound glutamine and lysine residues. These bonds are responsible for the crosslinking of large proteins and the incorporation of small primary amines into proteins. Transglutaminases are believed to be widely distributed in nature, since these crosslinks are found in both prokaryotic and eukaryotic cells. See generally, Folk, Ann. Rev. Biochem. 49:517-531, 1980.
Transglutaminase-catalyzed protein crosslinking reactions have been implicated in both normal and pathological processes in mammalian cells and tissues. The crosslink may act to maintain some forms of protein structure, such as in the terminal differentiation of epidermal cell layers and in other cellular architecture. An intracellular transglutaminase known as epidermal or Type I transglutaminase has been isolated and cloned from rabbit epithelial cells (Floyd and Jetten, Mol. Cell. Biol. 9:4846-4851, 1989), and a transglutaminase has been isolated and cloned from guinea pig liver cells (Ikura et al., Biochem. 27:2898-2905, 1988). Other transglutaminases include hair follicle transglutaminase, keratinocyte transglutaminase, prostate transglutaminase (Wilson et al., Fed. Proc. 38:1809, 1979), various microbial transglutaminases (U.S. Pat. Nos. 5,156,956 and 5,252,469), transglutaminase H (U.S. Pat. No. 5,726,051), and TGx (Aeschlimann et al., J. Biol. Chem. 273:3452-3460, 1998). Lee et al. (Prep. Biochem. 16:321-335, 1986) have described the purification of a transglutaminase from human erythrocytes. These transglutaminases have been shown to be distinct from a plasma transglutaminase, factor XIII, which stabilizes fibrin clots. DNAs encoding human and bovine factor XIII have been cloned and sequenced. See, Ichinose et al., Biochem. 25:6900-6906, 1986; Takahashi et al., Proc. Natl. Acad. Sci. USA 83:8018-8023, 1986; WIPO Publication WO 96/21025.
Transglutaminases have been employed for crosslinking purposes in a variety of fields. Certain microbial transglutaminases have found use in the food processing industry for enhancing the texture of processed foods, particularly cheese and fish products. See, for example, U.S. Pat. No. 6,100,053. Others have been used in enzyme-catalyzed fluorescent labeling of proteins, in the introduction of cleavable crosslinks, and in the solid-phase, reversible removal of specific proteins from biological systems. Factor XIII has been proposed for a variety of therapeutic uses, including treatment of subarachnoid hemorrhage (e.g., Thie et al., Neurochirurgia 34:107-110, 1991), neonatal intracranial hemorrhage (Shirahata et al., Thrombosis Res. 57:755-763, 1990), inflammatory bowel disease (Lorenz et al., Haemostasis 21:5-9, 1991), and postoperative bleeding (U.S. Pat. No. 5,607,917; Laohaprasit et al., Neurosurgery 32:630-633, 1993; Shainoff et al., J. Thorac. Carciovasc. Surg. 108:437-445, 1994), and as an immunosuppressant (U.S. Pat. No. 5,464,615).